Production of hydroxymethylfurfural

ABSTRACT

The invention provides a process for making hydroxymethylfurfural. A reaction mixture comprising a saccharide and a metal complex of an N-heterocyclic carbene is initially provided. The saccharide is then allowed to react at about 70° C. or below to form hydroxymethylfurfural. The saccharide may be a hexose or a mixture of hexoses, or a dimer, oligomer or polymer or copolymer of a hexose or a mixture thereof.

TECHNICAL FIELD

The present invention relates to a method of producinghydroxymethylfurfural.

BACKGROUND OF THE INVENTION

The present consumption of fossil fuels has led to significant levels ofenvironmental pollution and rapidly diminishing petrochemical reserves.The diminishing fossil fuel reserves and the globe warming effects havebecome major concerns. The search for sustainable, alternative energy isof critical importance.

Biofuels are highly attractive as the only sustainable source of liquidfuels currently. However, the replacement of petroleum feedstock bybiomass is limited by the lack of highly efficient methods toselectively convert carbohydrates to chemical compounds for the biofuelproduction. A practical catalytic process that can transform theabundant biomass into versatile chemicals would also provide thechemical industry with renewable feedstocks. Biomass-derivedcarbohydrates represent a promising carbon-based alternative as anenergy source and a sustainable chemical feedstock. However, moreefficient processes need to be developed for the selective conversion ofcarbohydrates into useful organic intermediates.

Substantial efforts have been recently devoted towards convertingbiomass to 5-hydroxymethylfurfural (HMF), a versatile and keyintermediate in biofuel chemistry and petrochemical industry. HMFproduction from sugars has been successfully conducted in water, aproticsolvents (e.g. dimethylsulfoxide (DMSO)), and biphasic systems usingacid catalysts such as mineral acids and solid acids. Ionic liquids havebeen used as solvents for this conversion using metal salts and othercatalysts. However, the large-scale production of HMF is still impededby the lack of cost-effective synthesis methods. The water-methylisobutyl ketone (MIBK) biphasic system developed by Dumesic et al. has agreat potential for industrial applications [(a) Y. Roman-Leshkov, J. N.Chheda, J. A. Dumesic, Science 2006, 312, 1933; (b) J. N. Chheda, Y.Roman-Leshkov, J. A. Dumesic, Green Chem. 2007, 9, 342; (c) G. W. Huber,J. N. Chheda, C. J. Barrett, J. A. Dumesic, Science 2005, 308, 1446; (d)R. M. West, Z. Y. Liu, M. Peter, C. A. Gartner, J. A. Dumesic, J. Mol.Catal. A Chem. 2008, 296, 18]. However, the strongly acidic conditionsand the high reaction temperature result in significant materialreplacement costs and energy consumption.

It has been demonstrated that transition metals are good catalysts forthe transformation of sugars to HMF in ionic liquids. However, theproduct extraction and system recovery processes still suffer from lowefficiencies.

Recently, much effort has been devoted towards converting biomass to5-hydroxymethylfurfural (HMF), a versatile and key intermediate inbiofuel chemistry and petroleum industry. HMF and its 2,5-disubstitutedfuran derivatives can replace key petroleum-based building blocks. Thereare currently a number of catalysts that are active towards thedehydration of sugars to form HMF. However, most of them promoteside-reactions that form undesired by-products and further rehydrationof HMF to form levulinic acid and formic acid. They are also oftenlimited to simple sugar feedstock, such as fructose.

Recent reports illustrate the use of 1-H-3-methyl imidazolium chloride(HMIM⁺Cl⁻) as a solvent and an acid catalyst to efficiently convertfructose to HMF with about 90% yield. However, such system has not beshown to convert glucose, which is a more stable and abundant sugarsource. Dumesic's group has developed a two-phase system(aqueous/organic phases) for the separation and stabilization of HMFproduct((a) Y. Roman-Leshkov, J. N. Chheda, J. A. Dumesic, Science 2006,312, 1933; (b) J. N. Chheda, Y. Roman-Leshkov, J. A. Dumesic, GreenChem. 2007, 9, 342). Zhang's group has reported a metal chloride/ionicliquid system that gives moderate to good HMF yields for both fructose(83% with Pt or Rh chloride, 65% with CrCl₂) and glucose (a record highof 68% with CrCl₂) (H. Zhao, J. E. Holladay, H. Brown, Z. C. Zhang,Science 2007, 316, 1597).

There is a need for an improved method for converting both fructose andglucose to HMF in good to excellent yields, for example over about 80%.There is also a need for an improved method for converting othersaccharides to HMF. There is also a need for a method for convertingreadily available saccharides into HMF at moderate temperatures,preferably at temperatures below the normal boiling point of suitableextraction solvents.

OBJECT OF THE INVENTION

It is an object of the present invention to substantially overcome or atleast ameliorate one or more of the above disadvantages. It is a furtherobject to at least partially satisfy at least one of the above needs.

SUMMARY OF THE INVENTION

In a first aspect of the invention there is provided a process formaking hydroxymethylfurfural comprising exposing a saccharide to a metalcomplex of an N-heterocyclic carbene.

The following options may be used in conjunction with the first aspect,either individually or in any suitable combination.

The saccharide may comprise a monosaccharide. It may comprise adisaccharide. It may comprise an oligosaccharide. It may comprise apolysaccharide. It may comprise (or may be) a mixture of any two or moreof these. The monosaccharide may comprise fructose, glucose or a mixtureof these. The disaccharide may be sucrose.

The exposing may be conducted in a dipolar aprotic solvent. The solventmay be, or may comprise, an ionic liquid. The ionic liquid may be, ormay comprise, an imidazolium salt (e.g. halide, for example chloride).It may be, or may comprise, 1-butyl-3-methylimidazolium chloride.

The metal complex may be a transition metal complex. It may be achromium complex or a titanium complex or a tungsten complex or amolybdenum complex or a nickel complex or a palladium complex or aruthenium complex or an aluminium complex, or it may be a mixture of anytwo or more of these. It may be a CrII complex or a CrIII complex.

The N-heterocyclic carbene may be monomeric. It may be dimeric. It maybe oligomeric. It may be polymeric. The metal complex of theN-heterocyclic carbene may be a metal complex of an N-imidazole carbenefor example a metal complex of a monomeric N-imidazole carbene or of apolymeric N-imidazole carbene.

The process may also comprise the step of generating the metal complexof the N-heterocyclic carbene. The step of generating the metal complexof the N-heterocyclic carbene may comprise reacting a nitrogenheterocycle salt with a base in the presence of a salt of the metal. Thebase may be potassium t-butoxide.

The process may additionally comprise isolating the hydroxymethylfurfural.

The monosaccharide may be fructose and the yield of hydroxymethylfurfural may be greater than about 80%. The monosaccharide may beglucose and the yield of hydroxymethyl furfural may be greater thanabout 70%.

The metal complex of an N-heterocyclic carbene may be recycled followingremoval of the hydroxymethylfurfural from the reaction mixture. In theevent that the exposing is conducted in an ionic liquid, said ionicliquid may be recycled following removal of the hydroxymethylfurfuralfrom the reaction mixture. The recycling may comprise heating thereaction mixture following removal of the hydroxymethylfurfuraltherefrom for sufficient time to remove volatile substances therefrom.

In one embodiment there is provided a process for makinghydroxymethylfurfural comprising exposing fructose, glucose or a mixtureof these to a chromium complex of an N-heterocyclic carbene in an ionicliquid.

In another embodiment there is provided a process for makinghydroxymethylfurfural comprising:

-   -   generating a chromium complex of an N-heterocyclic carbene; and    -   exposing fructose, glucose or a mixture of these to the chromium        complex of the N-heterocyclic carbene in an ionic liquid.

In another embodiment there is provided a process for makinghydroxymethylfurfural comprising:

-   -   reacting a nitrogen heterocycle with a base in the presence of a        chromium salt so as to generate a chromium complex of an        N-heterocyclic carbene; and    -   exposing fructose, glucose or a mixture of these to the chromium        complex of the N-heterocyclic carbene in an ionic liquid.

The invention also provides hydroxymethyl furfural when made by theprocess of the first aspect.

In a second aspect of the invention there is provided use of a metalcomplex of an N-heterocyclic carbene for making hydroxymethyl furfural.

In a third aspect of the invention there is provided use ofhydroxymethylfurfural made by the process of the first aspect forproducing a fuel, e.g. a biofuel.

In a fourth aspect of the invention there is provided a biofuel madeusing hydroxymethylfurfural which has been made by the process of thefirst aspect.

In a fifth aspect of the invention there is provided a process formaking hydroxymethylfurfural comprising:

-   -   (i) providing a reaction mixture comprising a saccharide and a        metal complex of an N-heterocyclic carbene wherein said        saccharide is a hexose or a mixture of hexoses, or a dimer,        oligomer or polymer or copolymer of a hexose or a mixture        thereof, and

(ii) allowing the saccharide to react in the reaction mixture to formhydroxymethylfurfural

wherein steps (i) and (ii) are conducted at about 70° C. or below.

The following options may be used in conjunction with the fifth aspect,either individually or in any suitable combination.

The saccharide may comprise a monosaccharide. The monosaccharide maycomprise fructose, glucose or a mixture of these.

The reaction mixture may additionally comprise an ionic liquid. Theionic liquid may be a solvent for the saccharide or for the metalcomplex or for both. The saccharide may be in solution in the ionicliquid. The metal complex may be in solution in the ionic liquid.

The process may be conducted as a two-phase process. The process may beconducted such that, during step (ii), the reaction mixture iscontinuously contacted with a solvent for hydroxymethylfurfural, or suchthat, during step (ii), the reaction mixture is intermittently contactedwith a solvent for hydroxymethylfurfural. Commonly the solvent isimmiscible, or substantially immiscible, with the ionic liquid. This maytherefore serve to extract the hydroxymethylfurfural into the solvent.

The reaction mixture may be contacted with a solvent forhydroxymethylfurfural after step (ii). In this case also the solvent maybe immiscible, or substantially immiscible, with the ionic liquid. Thusthis may also serve to extract the hydroxymethylfurfural into thesolvent.

The metal complex of the N-heterocyclic carbene may be a metal complexof a monomeric N-heterocyclic carbene. It may be a metal complex of animidazol-2-ylidene or of an imidazolin-2-ylidine.

The metal complex may be a tungsten complex, a titanium complex, azirconium complex, a ruthenium complex or a mixture of any two or moreof these types of complex. It may be for example a tungsten complex ofan imidazol-2-ylidene or of an imidazolin-2-ylidine.

The process may comprise the step of generating the metal complex of theN-heterocyclic carbene. This step may comprise reacting a nitrogenheterocycle salt with a base in the presence of a salt of the metal. Thebase may be for example potassium t-butoxide. The process may compriseremoving a solvent in which said step of generating is conducted, saidremoving being conducted after said generating. In this case thereaction mixture may be made using the resulting dried metal complex ofthe N-heterocyclic carbene. Alternatively the solvent may not beremoved, and the reaction mixture may be made using a solution of themetal complex of the N-heterocyclic carbene in the solvent.

The process may be conducted as a continuous reaction. It may beconducted as a continuous batch reaction.

The metal complex of the N-heterocyclic carbene may be recycledfollowing removal of the hydroxymethylfurfural from the reactionmixture. The ionic liquid (if present) may be reused following removalof the hydroxymethylfurfural from the reaction mixture.

The process may be conducted under non-acidic conditions. It may beconducted at approximately neutral pH. It may be conducted under basicconditions. It may be conducted under substantially non-aqueousconditions. In this context “non-aqueous” should be taken to indicatesimply that water is not intentionally added as a solvent. It will berecognised that small amounts of water may nevertheless be present in aprocess as described herein.

In an embodiment, there is provided a process for makinghydroxymethylfurfural comprising:

-   -   (i) providing a reaction mixture comprising a saccharide and a        metal complex of a 1,3-disubstituted imidazol-2-ylidine in an        ionic liquid, wherein said saccharide is fructose, glucose or a        mixture of these; and    -   (ii) allowing the saccharide to react in the reaction mixture to        form hydroxymethylfurfural,        wherein steps (i) and (ii) are conducted at about 70° C. or        below and wherein the metal complex is selected from the group        consisting of a tungsten complex, a titanium complex, a        zirconium complex, a ruthenium complex and a mixture of any two        or more of these types of complex.

In another embodiment, there is provided a process for makinghydroxymethylfurfural comprising:

-   -   (i) reacting an N,N′-disubstituted imidazolium salt with a base        in the presence of a salt of a metal, said metal being selected        from the group consisting of tungsten, titanium, zirconium,        ruthenium and a mixture of any two or more of these, so as to        produce a complex of the metal with a 1,3-disubstituted        imidazol-2-ylidine derived from said N,N′-disubstituted        imidazolium salt;    -   (ii) providing a reaction mixture comprising a saccharide and        the metal complex of the 1,3-disubstituted imidazol-2-ylidine in        an ionic liquid, wherein said saccharide is fructose, glucose or        a mixture of these; and    -   (iii) allowing the saccharide to react in the reaction mixture        to form hydroxymethylfurfural,        wherein steps (ii) and (iii) are conducted at about 70° C. or        below.

In another embodiment there is provided a process for makinghydroxymethylfurfural comprising:

-   -   (i) providing a reaction mixture comprising a saccharide and a        metal complex of an N-heterocyclic carbene in an ionic liquid,        wherein said saccharide is a hexose or a mixture of hexoses, or        a dimer, oligomer or polymer or copolymer of a hexose or a        mixture thereof and wherein said first and second solvents are        sufficiently immiscible that the reaction mixture is a two phase        reaction mixture; and    -   (ii) allowing the saccharide to react in the reaction mixture to        form hydroxymethylfurfural while continuously or intermittently        contacting the reaction mixture with a solvent for        hydroxymethylfurfural, said solvent being immiscible with the        ionic liquid;        wherein steps (i) and (ii) are conducted at about 70° C. or        below. In this embodiment, the metal may be selected from the        group consisting of tungsten, titanium, zirconium, ruthenium and        a mixture of any two or more of these. It may be for example        tungsten, in which case steps (i) and (ii) may be conducted at        about 50° C.

In another embodiment, there is provided a process for makinghydroxymethylfurfural comprising:

-   -   (i) reacting an N,N′-disubstituted imidazolium salt with a base        in the presence of a salt of a metal, said metal being selected        from the group consisting of tungsten, titanium, zirconium,        ruthenium and a mixture of any two or more of these, so as to        produce a complex of the metal with a 1,3-disubstituted        imidazol-2-ylidine derived from said N,N′-disubstituted        imidazolium salt;    -   (ii) providing a reaction mixture comprising a saccharide and        the metal complex of the 1,3-disubstituted imidazol-2-ylidine in        an ionic liquid, wherein said saccharide is fructose, glucose or        a mixture of these; and    -   (iii) allowing the saccharide to react in the reaction mixture        to form hydroxymethylfurfural while continuously or        intermittently contacting the reaction mixture with a solvent        for hydroxymethylfurfural, said solvent being immiscible with        the ionic liquid,        wherein steps (ii) and (iii) are conducted at about 70° C. or        below.

In another embodiment, there is provided a process for makinghydroxymethylfurfural comprising:

-   -   (i) reacting an N,N′-disubstituted imidazolium salt with a base        in the presence of a tungsten salt so as to produce a tungsten        complex of a 1,3-disubstituted imidazol-2-ylidine derived from        said N,N′-disubstituted imidazolium salt;    -   (ii) providing a reaction mixture comprising a saccharide and        the tungsten complex of the 1,3-disubstituted imidazol-2-ylidine        in an ionic liquid, wherein said saccharide is fructose, glucose        or a mixture of these; and    -   (iii) allowing the saccharide to react in the reaction mixture        to form hydroxymethylfurfural while continuously or        intermittently contacting the reaction mixture with a solvent        for hydroxymethylfurfural, said solvent being immiscible with        the ionic liquid,        wherein steps (ii) and (iii) are conducted at about 50° C.

In a sixth aspect of the invention there is provided a process formaking a fuel comprising:

-   -   (i) providing a reaction mixture comprising a saccharide and a        metal complex of an N-heterocyclic carbene wherein said        saccharide is a hexose or a mixture of hexoses, or a dimer,        oligomer or polymer or copolymer of a hexose or a mixture        thereof,    -   (ii) allowing the saccharide to react in the reaction mixture to        form hydroxymethylfurfural; and    -   (iii) converting the hydroxymethylfurfural to the fuel;        wherein steps (i) and (ii) are conducted at about 70° C. or        below.

The process may comprise the step of separating thehydroxymethylfurfural from the reaction mixture prior to step (iii). Themetal complex of an N-heterocyclic carbene may be for example a tungstencomplex of an imidazol-2-ylidene or of an imidazolin-2-ylidine.

BRIEF DESCRIPTION OF THE DRAWINGS

A preferred embodiment of the present invention will now be described,by way of an example only, with reference to the accompanying drawingswherein:

FIG. 1 is a graph showing the effect of reaction temperature on HMFyield from (▪) fructose and (♦) glucose over 9 mol % of 6-CrCl₂(substrate/BMIM weight ratio=0.2, 6 h);

FIG. 2 is a graph showing the effect of reaction time on HMF yield from(▪) fructose and (♦) glucose over 9 mol % of 6-CrCl₂ (substrate/BMIMweight ratio=0.2, 100° C.);

FIG. 3 is a graph showing the effect of 6-CrCl₂ loading on HMF yieldfrom (▪) fructose and (♦) glucose (substrate/BMIM weight ratio=0.2, 6 h,100° C.);

FIG. 4 is a graph showing the effect of substrate loading on HMF yieldfrom (▪) fructose and (♦) glucose over 9 mol % of 6-CrCl₂ (6 h, 100°C.);

FIG. 5 is an XPS spectrum of the reaction intermediate of 6-CrCl₂;

FIG. 6 shows a graph of: (▪) Fructose conversion, () HMF yield, and (

) sum of fructose and HMF masses as a function of time for fructosedehydration (dashed curve)—reaction conditions: 0.05 mmol of Ipr-WCl₆,500 mg of BMIMCl, 100 mg of fructose, 50° C.;

FIG. 7 shows a schematic of (A) batch process, and (B) continuous batchprocess, for fructose conversion to HMF in the THF-BMIMCl biphasicsystem; and

FIG. 8 is a graph showing HMF yield from the continuous batch processusing the THF-BMIMCl biphasic system—reaction conditions for the firstbatch: 100 mg of fructose, 5 mol % of Ipr-WCl₆, 500 mg of BMIMCl, 10 mlof THF (refreshed 3 times), 50° C., 6 h; 100 mg of fructose were addeddirectly after 6 h for the subsequent batches.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The inventors have found that N-heterocyclic carbene-metal complexes arecapable of catalysing the conversion of saccharides such as glucose orfructose to hydroxymethylfurfural (5-(hydroxymethyl)-2-furaldehyde;HMF). The reaction proceeds in relatively high yield, particularly whenan ionic liquid solvent is employed. Mixtures of suitable saccharidesmay also be used. The reaction may be used with monosaccharides (e.g.glucose, fructose), disaccharides (e.g. sucrose), oligosaccharides orpolysaccharides (e.g. starch, cellulose). The saccharide may be a hexoseor a mixture of hexoses, or a dimer, oligomer or polymer or copolymer ofa hexose or a mixture thereof. The reaction described herein has theadvantage that it uses relatively inexpensive and/or readily availablesubstrates, which, in some cases, represent waste materials. Forexample, 30% HMF yield was achieved by conversion of cellulose accordingto the process of the invention. Polymeric NHC based catalysts werefound to provide slightly lower HMF yields from fructose and glucosethan their monomeric counterparts, however the polymeric NHC basedcatalysts have the advantage of better recyclability than the monomericcounterparts. The N-heterocyclic carbene-metal complex may be used inconjunction with an acid catalyst. The acid catalyst may be aheterogeneous acid catalyst. It may be a solid heterogeneous acidcatalyst. It may for example be a zeolite. This may be particularlybeneficial in cases where the saccharide is a disaccharide,oligosaccharide or polysaccharide. The process may comprise hydrolysisof the disaccharide, oligosaccharide or polysaccharide. The hydrolysismay be an in situ hydrolysis. It may be catalysed by the acid catalyst.

Suitable solvents for the process are dipolar aprotic solvents. Thesolvent may comprise, or may be, an ionic liquid. A suitable ionicliquid is 1-butyl-3-methylimidazolium chloride. Other imidazolium saltsare also suitable. The counterion of the imidazolium salt may be ahalide, for example chloride. The solvent may be a mixture of solvents,for example a mixture of dipolar aprotic solvents. The solvent maycomprise an ionic liquid together with a different dipolar aproticsolvent (such as dimethylformamide, dimethylsulfoxide,hexamethylphosphoramide etc.) The solvent may primarily consist of theionic liquid, e.g. greater than about 50%, or greater than about 60, 70,80 or 90% by weight or volume.

The metal complex of the N-heterocyclic carbene may be a metal complexof an N-imidazole carbene. It may be a chromium II or chromium IIIcomplex of an N-heterocyclic carbene. The N-heterocyclic carbene (NHC)may be derived from imidazolium salt, or from a substituted imidazoliuimsalt, in particular an N,N′-disubstituted imidazolium salt. Theimidazolium salt may be a bisimidazolium salt, e.g. a pyridinebisimidazolium salt. The NHC may be derived from an imidazolinium salt,or from a substituted imidazolinium salt in particular anN,N′-disubstituted imidazolinium salt. The imidazolinium salt may be aimidazolinium salt, e.g. a pyridine imidazolinium salt. The NHC may bean α,α′-dinitrogen carbon. Each of the a-nitrogen atoms may besubstituted. They may each, independently, be substituted with a bulkygroup. They may both substituted with a bulky group (optionally with thesame bulky group). Suitable bulky groups are t-butyl, neopentyl,2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 2,6-diisopropylphenyl,2,4,6-triisopropylphenyl etc. The substituents on the nitrogen atoms maybe, independently, alkyl groups or aryl groups or heteroaryl groups.Thus the NHC may be an imidazol-2-ylidene. It may be anN,N′-disubstituted imidazol-2-ylidine, i.e. a 1,3-disubstitutedimidazol-2-ylidine. It may be an imidazolin-2-ylidine. It may be anN,N′-disubstituted imidazolin-2-ylidine, i.e. a 1,3-disubstitutedimidazolin-2-ylidine.

The metal complex of the N-heterocyclic carbene may be soluble in thesolvent (or in the reaction mixture) or it may be insoluble therein. Itmay be used as a homogeneous catalyst or as a heterogeneous catalyst.Particularly in the case of a polymeric complex, it may be used as aheterogeneous catalyst. If the complex is used as a heterogeneouscatalyst, it may, optionally, subsequently be removed from the reactionmixture by precipitation, filtration, centrifugation or some combinationof these. It may then be reused in a subsequent reaction if desired. Itmay be reused with a loss of catalytic activity of less than about 10%,or less than about 5, 2 or 1%.

The metal complex of the N-heterocyclic carbene may be generated fromthe corresponding nitrogen heterocycle salt by reaction with a base inthe presence of a salt of the metal. The base may be potassiumt-butoxide or some other strong base, for example sodium hydride,potassium hydride, NaN(TMS)₂ etc. The base may be a sufficiently strongbase to be capable of converting the nitrogen heterocycle salt to thecorresponding N-heterocyclic carbene. Thus for example to generate ametal complex of a 1,3-disubstituted imidazol-2-ylidine, thecorresponding 1,3-disubstituted imidazolium salt may be treated with astrong base in the presence of a salt of the metal. The nitrogenheterocycle salt may be a halide, e.g. chloride, bromide or iodide, ormay have some other counterion. The salt of the metal may be a halide,e.g. chloride, bromide or iodide, or may have some other counterion. Thecounterion of the salt of the metal may be the same as or different tothe counterion of the nitrogen heterocycle salt. The metal may be atransition metal. The metal may be chromium, titanium, tungsten,molybdenum, nickel, palladium, ruthenium or aluminium, or may be amixture of any two or more of these. The reaction may be conducted in asolvent. The solvent may be a dipolar aprotic solvent. It may be asolvent that is not base sensitive. It may be for example DMF, DMSO,HMPT, HMPA or some other suitable solvent. It may be a solvent for theheterocycle salt. It may be a solvent for the base. It may be a solventfor the metal salt. It may be a solvent for the metal complex of theNHC. It may be desirable to heat the reaction mixture in order to formthe metal complex of the NHC. In some cases heating may not be used.Suitable temperatures are between about 20 and about 100° C., or about30 to 100, 50 to 100, 20 to 80, 20 to 50, 30 to 70, 50 to 80, 70 to 100or 70 to 90° C, e.g. about 20, 30, 40, 50, 60, 70, 80, 90 or 100° C. Thereaction may be conducted for sufficient time for substantially completeconversion. It may be conducted for about 1 to about 6 hours, or about 1to 3, 3 to 6 or 2 to 5 hours, e.g. about 1, 2, 3, 4, 5 or 6 hours. Thetemperature and time should be sufficient to form the metal complex ofthe NHC.

In the process of the invention, the sugar (fructose and/or sucrose) maybe mixed with the solvent (e.g. ionic liquid). A suitable ratio of sugarto solvent is about 20% w/w, or about 5 to about 30%, or about 5 to 25,5 to 20, 5 to 10, 10 to 30, 20 to 30, 10 to 25 or 15 to 25%, e.g. about5, 10, 15, 20, 25 or 30%. In the case of glucose as substrate, this maybe as high as 50, 60, 70, 80, 90 or even 100% (e.g. may also be about40, 50, 60, 70, 80, 90 or 100% w/w). The catalyst (metal-carbenecomplex) may then be added. A suitable addition ratio may be about 1 toabout 15 mol % relative to the sugar, or about 1 to 10, 1 to 5, 5 to 15,10 to 15, 5 to 10, 1 to3, 2 to 5 or 2 to 4%, e.g. about 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 mol %. The addition ratio should besufficient to obtain an acceptable, optionally an optimal, yield ofproduct. The reaction may be conducted at a temperature of about 80 toabout 120° C., or about 80 to 100, 80 to 90, 90 to 120, 100 to 120 or 90to 100° C., e.g. about 80, 85, 90, 95, 100, 105, 110, 115 or 120° C., orat some other suitable temperature. The temperature may be selected soas to provide an optimum yield or to obtain an acceptable yield. It maybe selected to provide a trade-off between poor yield and excessiveby-product formation. It may be selected to provide an acceptably lowyield of by-product. The reaction may be conducted for between about 2and about 10 hours, or about 2 to 8, 2 to 6, 4 to 10, 6 to 10, 4 to 8 or5 to 7 hours, or about 2, 3, 4, 5, 6, 7, 8, 9 or 10 hours. The time maydepend on the temperature. The reaction may be conducted under an inertatmosphere, e.g. nitrogen, carbon dioxide, helium, neon, argon or amixture of any two or more of these, or it may be conducted in air orsome other oxygen containing gas mixture. In some cases it may beconducted under reduced pressure, e.g. an absolute pressure of about 0.2atmospheres or less, or about 0.1, 0.05, 0.02 or 0.01 atmospheres orless. In such cases at least some byproducts may be removed as they areformed. This may enable recycling of the metal complex of theN-heterocyclic carbene and/or of the solvent without a separate step ofremoving the volatiles.

The hydroxymethylfurfural product may be isolated from the reactionmixture by known methods. These include solvent extraction (e.g. diethylether extraction), water washing, column chromatography, gaschromatography, hplc or a combination of any two or more of these.

The reaction may be conducted using fructose as a substrate, or glucose,or with a mixture of the two. If suitable conditions are used (asdescribed above), a yield of hydroxymethyl furfural may be at leastabout 70%, or at least about 75, 80, 85 or 90%. Commonly the yield fromglucose and from glucose will be different.

The metal complex of an N-heterocyclic carbene may be recycled followingremoval of the hydroxymethylfurfural from the reaction mixture. Inparticular, it may be reused in a subsequent reaction, said subsequentreaction being the process for making hydroxymethylfurfural describedherein. This provides cost savings in the process and can be achievedwith little or no loss of yield of hydroxymethyl furfural (e.g. lessthan about 5%, loss of yield, or less than about 4, 3 or 2% loss ofyield). In the event that the exposing is conducted in an ionic liquid,the ionic liquid may also be recycled. Commonly, the producthydroxymethylfurfural is removed from the reaction mixture by solventextraction (optionally repeated solvent extraction). The reactionmixture (with the hydroxymethyl furfural removed) may then be treated soas to remove volatile materials (e.g. substantially all volatilematerials, or at least about 80, 85, 90, 95 or 98% of volatilematerials) by heating and/or applying a vacuum thereto. Alternatively oradditionally, removal of volatiles may be conducted prior to removal ofthe hydroxymethylfurfural. In this context, “volatile” materials areconsidered to have a boiling point of about 100° C. or less. The heatingmay be at a temperature of about 80 to about 150° C., or about 80 to120, 80 to 100, 100 to 150, 120 to 150, 100 to 120 or 90 to 110° C.,e.g. about 80, 90, 100, 110, 120, 130, 140 or 150° C. The vacuum mayhave an absolute pressure of about 0.2 atmospheres or less, or about0.1, 0.05, 0.02 or 0.01 atmospheres or less. The time for said treatingmay be sufficient under the treatment conditions to remove the desiredproportions of volatile materials. It may be about 1 to about 5 hours,or about 1 to 3, 2 to 5 or 1.5 to 2.5 hours, e.g. about 1, 1.5, 2, 2.5,3, 3.5, 4, 4.5 or 5 hours. The heating/vacuum may be applied in asuitable apparatus, e.g. a vacuum chamber, a cyclone evaporator or someother suitable apparatus. In some cases no vacuum is applied.

The production of hydroxymethylfurfural according to the presentinvention may be conducted as a continuous process. In an example,saccharide(s) and catalyst are continuously added to an addition zone ofa reaction cycle, the resulting mixture is then held at a suitabletemperature for a suitable time (as described earlier) for reaction toform hydroxymethylfurfural in a reaction zone of the reaction cycle,volatiles and hydroxymethylfurfural are continuously separated in aseparation zone and the solvent and catalyst recycled to the additionzone for reuse. The reaction zone may have vacuum applied to it, so thatvolatiles are removed during the reaction, and hydroxymethylfurfural isremoved subsequently in the separation zone.

Thus in many embodiments the present invention presents a newCr—N-heterocyclic carbene (NHC)/ionic liquid system that selectivelyproduces hydroxylmethylfurfural (HMF) from glucose and fructose. Thisnovel catalyst achieved the highest efficiency known from both fructoseand glucose feedstocks. The HMF yields were as high as 96% and 82% fromfructose and glucose respectively. The new system provided highselectivity towards HMF, and tolerance towards high substrate loading.It also allowed for ease of recycling of catalyst and ionic liquid.

The inventors have investigated N-heterocyclic carbene (NHC)-metalcomplexes as catalysts for the sugar dehydration reaction. These ligandsoffered a great deal of flexibility towards modifying the catalyticactivity by varying the stereo and electronic properties of NHCs. Theconversions of fructose and glucose were tested over1-butyl-3-methylimidazolium chloride (BMIM) with different catalysts(Scheme 1). The NHC-metal complexes were pre-generated by mixingimidazolium salts, KO^(t)Bu and metal chlorides in N,N-dimethylformamide(DMF) under heating for several hours before adding to the reactionsystem. In a typical reaction protocol, 100 mg of sugar was mixed with500 mg of BMIM and 2 mol % pre-prepared Cr—NHC catalyst. The reactionmixture was kept at 100° C. for 6 h. HMF was extracted by ether (threetimes). All experiments were repeated, and the HMF yield was confirmedby both GC and NMR of the isolated product.

Several metals were selected for the screening studies, but only Cr(II)and Cr(III) gave promising results. Unlike the previously reported metalchloride/ionic liquid system, herein Cr(II) and Cr(III) showed similaractivities toward converting fructose or glucose to HMF (Table 1).

TABLE 1 Conversion of sugars to HMF by NHC-Cr catalysts.^(a) Yield fromglucose Yield from fructose (%)^([b]) (%)^([b]) entry catalyst BMIM DMSOBMIM DMSO  1 1-CrCl₂ 65 28 66 25  2 2-CrCl₂ 68 32 65 25  3 3-CrCl₂ 76 3962 26  4 4-CrCl₂ 89 52 90 31  5 5-CrCl₂ 76 — 50 —  6 6-CrCl₂ 96 41 81 32 7 7-CrCl₂ 93 — 70 26  8 8-(CrCl₂)₂ — — 81 —  9 8-CrCl₂ 74 — 14 — 104-CrCl₃ 90 40 78 30 11 5-CrCl₃ 77 — 72 — 12 6-CrCl₃ 96 40 78 32 137-CrCl₃ 83 — 81 — 14^([c]) 6-CrCl₃ 82 — 65 — 15^([d]) 6-CrCl₃ — — 76 —16^([e]) 6-CrCl₃ 96 — 76 — 17^([f]) 6-CrCl₃ 98 — 76 — ^([a])Reactionconditions: 500 mg of solvent, 50 mg of sugar, 9 mol % of catalyst, 100°C., 6 h, in air, unless otherwise stated. ^([b])Yield was determined bygas chromatography (GC) with internal standard and isolated pureproduct. ^([c])Reaction was conducted under argon. ^([d])9 mol % ofbipyridine was added to the reaction system. ^([e])Recycled reactionsystem from entry 12. ^([f])Recycled reaction system from entry 16.

Structures of carbenes used in the reactions summarised in Table 1 areshown below.

Remarkably, catalyst activity was found to be closely related to thestereo property of the NHC ligands. 1-CrCl₂ catalyzed the dehydrationfructose and glucose with HMF yields of 65% and 66%, respectively (Table1). Catalyst with the isopropyl-substituted NHC ligand, 2-CrCl₂, showedsimilar efficiency as 1-CrCl₂. In contrast, the HMF yields from sugarswere significantly increased using chromium catalysts with the morebulky NHC ligands, such as 3-7. 6-CrCl₂ system provided a HMF yield ashigh as 96% from fructose. It also gave a HMF yield of 81% from glucose,which was a record high efficiency for glucose feedstock. There was nodifference in yield for the metal catalysts with saturated vs.unsaturated NHC ligands. The catalysts with the most bulky NHC ligand,1,3-bis(2,6-diisopropylphenyl)imidazolylidene 6 and1,3-bis(2,6-diisopropyl)phenylimidazolinylidene 7 provided the highestyields. To better understand the details of this reaction, bidentateligand 8 was examined. Interestingly, catalyst 8-(Cr)₂ gave a good HMFyield (81%) from glucose, while 8-(Cr)₁ showed a poor HMF yield (14%).These results suggested that an over-crowded complex would have a loweractivity in binding with substrates and initiating the reaction. Controlreaction without catalyst showed a very low HMF yield (less than 40% and1% from fructose and glucose, respectively). The reaction temperaturewas investigated between 80 ° C. and 100° C. for both fructose andglucose. Lower temperature led to a lower HMF yield: higher temperaturegave rise to byproducts, mainly diformylfuran (DFF) (see FIG. 1).

Kinetics studies of this reaction over 6-CrCl₂ showed that the HMF yieldpeaked at our standard reaction condition of 6 h for both fructose andglucose (see FIG. 2). The HMF yield gradually decreased at reactionperiods beyond 6 h. This could be due to the slow decomposition of HMFin the reaction system. HMF yield for fructose and glucose after 6 hbegan to decrease as the NHC—Cr catalyst loading was reduced to lessthan 1 mol % (see FIG. 3). Generally, lower catalyst loading wouldrequire a longer reaction time to achieve a high conversion. However, inthis system, the product could decompose under the reaction condition,so longer reaction time would lead to lower yield of the desiredproduct. Thus, if a low catalyst loading of 1 mol % is to be employed,other reaction conditions have to be optimized to maximize the HMFyield.

The substrate/solvent weight ratio was also found to be important forthe overall efficiency of the reaction system (see FIG. 4). When thefructose/BMIM weight ratio was increased from 0.05 to 0.2, the HMF yieldchanged slightly from 95% to 94%. As the fructose/ionic liquid weightratio increased from 0.2 to 0.5, the HMF yield decreased substantiallyto 70%. Further increase in the fructose/ionic liquid weight ratio didnot lead to significant variation in HMF yield. Remarkably, the HMFyields remained rather unaffected (81-77%) as the glucose/BMIM weightratio was varied from 0.05 to 0.67. The HMF yield was only slightlydecreased (to 73%) when the glucose/BMIM weight ratio was increased to1.0. In this case, BMIM acted more like an assisting reagent than asolvent.

The different behavior of fructose and glucose in FIG. 4 suggesteddifferent possible reaction mechanisms for the two feedstocks. In thelatter, glucose might be first converted to fructose and subsequently toHMF over the NHC—Cr catalyst (see Scheme 2). In this case, fructoseconcentration would be relatively low even when the glucose substrateloading was high since fructorse was merely an intermediate in theconversion of glucose to HMF. Interestingly, HMF yields of about 15%lower were obtained for the reaction conducted in argon vs. in air(Table 1, entry 14 vs. entry 12). The NHC—Cr catalysts were also testedin dimethylsulfoxide (DMSO). Much lower HMF yields were obtained fromfructose (28-52%) and glucose (25-32%) in this solvent (see Table 1).Again, catalysts with bulky NHC ligands showed higher efficiency in theDMSO system.

The high efficiency of the catalyst and the high substrate loadingrender the process of the invention very attractive for industrialscale-up. This reaction process would also allow for the continuousextraction of product, and the recycling of catalyst NHC—Cr and ionicliquid. HMF would be the sole product in ether extraction when theconversion of glucose and fructose was conducted at temperatures below100° C. After the ether extraction, the reaction medium was pre-heatedat 100° C. for 2 h to remove the low boiling point components, such asether and water, and then directly used in the next run by adding thesugar substrate. The recycled reaction system retained high activity inthe conversion of glucose and fructose to HMF (Table 1, entries 16 and17). The high substrate loading and the ease of catalyst and ionicliquid recycling make this system attractive for industrialapplications.

The present results clearly suggested that NHC—CrCl_(x) complexes play akey role in glucose dehydration in BMIM. Bulky NHC ligand preventedchromium from forming multiple NHC coordination in BMIM, reducing thecatalytic activity as in the case of 8-(Cr)₁. In contrast, no inhibitioneffect was observed with the addition of bipyridine ligand in the caseof 6-CrCl₃ (HMF yield of 76% from glucose) (Table 1, entry 15). Glucoseis proposed to be converted to fructose or HMF by NHC—Cr complex viaredox processes (see Scheme 2). This may explain why chromium, which hasversatile oxidation states, is suitable for this reaction. X-rayphotoelectron spectroscopy (XPS) indicated split peaks for Cr 2p_(3/2)and 2p_(1/2) peaks for the reaction intermediate of 6-CrCl2. Theshoulder of Cr 2p_(3/2) and Cr 2p_(1/2) peaks at 577 eV and 587 eV,respectively, indicated the presence of oxidized Cr species (see FIG.5).

In summary, a new NHC—Cr/ionic liquid system has been developed for theselective conversion of sugars to HMF. This new system achievedexcellent efficiency and the highest HMF yields reported thus far forboth fructose and glucose feedstocks. The HMF yields were as high as 96%and 82% for fructose and glucose, respectively. The new system alsoallowed for ease of catalyst and ionic liquid recycling, provided soleHMF product by simple extraction, and was tolerant towards highsubstrate loading.

The ionic liquid-metal catalyst system described above has excellentstability and selectivity in HMF conversion from carbohydrates. However,the process described above is limited to batch reaction protocols dueto the incompatibility of the high reaction temperature (80-120° C.) andthe commonly used extraction method using diethyl ether, a low boilingpoint solvent.

In an adaptation of the above process for making hydroxymethylfurfural,a reaction mixture comprising a saccharide and a metal complex of anN-heterocyclic carbene is prepared. As described earlier, the saccharidemay be a hexose or a mixture of hexoses, or it may be a dimer, oligomeror polymer or copolymer of a hexose or a mixture thereof. Details ofsuitable saccharides have been described earlier in this specification.The saccharide is then allowed to react in the presence of the metalcomplex in the reaction mixture so as to form hydroxymethylfurfural. Byuse of suitable reaction conditions and metal complex, this reaction maybe conducted at about 70° C. or below. It may be conducted at or belowabout 65, 60, 55, 50, 45, 40, 35, 30, 25 or 20° C, or at about 20 toabout 70° C, or about 20 to 50, 20 to 40, 20 to 30, 30 to 50, 40 to 50,50 to 70, 40 to 60 or 30 to 40° C. The time required reaction willdepend in part on factors such as the temperature, the nature of thecatalyst, the catalyst concentration, the desired degree of conversion,the nature of the saccharide etc. In general the time taken will becomparable to that described earlier (i.e. about 1 to about 6 hours)although in some cases it may be longer than this, e.g. up to about 12hours. Unless separately described, the conditions used for thisadaptation (i.e. at or below 70° C.) are the same as those for theprocess described earlier in this specification. The adapted process maybe capable of producing HMF at relatively low temperature (as describedabove) with a yield from fructose of at least about 40%, or at leastabout 45, 50, 55 or 60%. The process may be adapted to operatecontinuously so as to continuously produce HMF.

The reaction mixture may be a two phase reaction mixture. This hasseveral potential advantages including:

-   -   it facilitates continuous or semi-continuous operation; and/or    -   it facilitates reuse/recycling of the metal complex; and/or    -   it facilitates separation of the product; and/or    -   higher yield of HMF.

The two phase reaction mixture commonly comprises a reaction mixturephase and an extraction solvent phase. The reaction is commonlyconducted below the normal boiling point of the extraction solvent.Commonly the reaction mixture phase comprises an ionic liquid, which mayfunction as a solvent for the reaction. Thus the saccharide and/or themetal complex may be dissolved in the ionic liquid in the reactionmixture phase. Suitable solvents are described earlier in thespecification as solvents for the process. The second phase of the twophase reaction mixture is an extraction solvent phase, i.e. it comprisesan extraction solvent. The extraction solvent preferably is capable ofdissolving the HMF produced in the reaction. Preferably the saccharideand/or the metal complex has low solubility (or is insoluble) in theextraction solvent. Thus the extraction solvent may be capable ofextracting the HMF from the reaction mixture phase without substantiallyextracting saccharide and/or metal complex. The extraction solvent maybe substantially incapable of extracting an intermediate formed from thesaccharide, said intermediate being convertible under the conditions ofthe process into HMF. The extraction solvent may be such that thesolubility of HMF in the extraction solvent is greater than itssolubility in the reaction mixture (e.g. in the ionic liquid). Theextraction solvent may be a dipolar aprotic solvent. It may be an ether,e.g. a cyclic ether. It may be for example THF. It may have a boilingpoint below that of the reaction temperature.

In the above discussion it will be understood that the two phases mayhave a finite but low miscibility. The miscibility may be sufficientlylow that the reaction mixture forms a two phase reaction mixture at thetemperature used in the reaction. The miscibility of the reactionmixture phase in the extraction solvent phase, or, independently, of theextraction solvent phase in the reaction mixture phase, may be less thanabout 10% at the temperature used in the reaction, or less than about 5,2 or 1%. It may be about 0.1 to about 10%, or about 0.1 to 5, 0.1 to 1,0.1 to 0.5, 0.5 to 10, 1 to 10, 5 to 10, 1 to 5 or 0.5 to 2%, e.g. about0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9or 10%.

The N-heterocyclic carbene may be a monomeric N-heterocyclic carbene.Suitable N-heterocyclic carbenes have been discussed earlier in thisspecification. In some embodiments a co-catalyst is used. The cocatalystmay be an acidic cocatalyst. It may be a heterogeneous cocatalyst. Itmay for example be a zeolite, e.g. zeolite H—Y (CBV720)

The metal complex may be a tungsten complex or a titanium complex or azirconium complex or a ruthenium complex or a mixture of any two or moreof these types of complex. The metal complex of the N-heterocycliccarbene may be a metal complex of an N-imidazole carbene. It may becomplex with a metal such that said complex is capable of catalysing theprocess at less than about 70° C. The metal may be complexed to thecarbene portion of the NHC.

The process may comprise the step of generating the metal complex of theN-heterocyclic carbene. This process has been described earlier. The NHCmay be used as a solution in the solvent in which it is generated, orthe solution in which it is generated may be dried and the dried NHCmetal complex may be used in the process (i.e. to form the reactionmixture). The metal complex may be made from a salt of the metal. In theevent that the metal is tungsten, it may be made from a W(IV) salt or itmay be made from a W(VI) salt, or it may be made from a mixture of thetwo.

The process may additionally comprise isolating thehydroxymethylfurfural. As discussed earlier, an advantage of the lowerreaction temperature is that it allows for extraction of thehydroxymethyl furfural during the course of the reaction. In one optionthe reaction mixture is extracted with a solvent after completion of thereaction as before, optionally after cooling the reaction mixture belowthe reaction temperature used (although in some embodiments the reactionmixture is not cooled, as the extraction solvent has a boiling point ator above the reaction temperature). In another option, however, HMF isremoved from the reaction mixture as the reaction is proceeding. This istermed herein a two phase system. Removal of HMF from the reactionmixture may serve to drive the reaction forwards so as to improve theyield of HMF. In some embodiments the reaction mixture is continuouslyextracted by the extraction solvent. This may be achieved for example byuse of a continuous countercurrent extractor. It may be achieved byconducting the reaction in a two phase system in which the extractionsolvent in contact with the reaction mixture phase is continuouslyremoved and fresh extraction solvent added. In some embodiments, theremoved extraction solvent (containing HMF) is treated (e.g. evaporated)so as to regenerate fresh extraction solvent which may then recycled tocontact with the reaction mixture phase. This may also serve to isolatethe crude HMF product. In other embodiments the extraction is notcontinuous. For example, at regular intervals (i.e. intermittently) theextraction solvent phase may be removed (either partially orsubstantially completely) from the reaction mixture phase and replacedwith a fresh aliquot of extraction solvent. As described above for thecontinuous option, in the intermittent option the extraction solvent maybe recycled into the two phase system. The two phase reaction system maybe agitated (stirred, shaken, sonicated or similar) in order to promotereaction of saccharide or extraction of HMF or both. Alternatively thesystem may be substantially unagitated, so as to promote separation ofthe phases.

In some embodiments the saccharide is fed continuously or intermittentlyto the reaction mixture. This embodiment may be used in conjunction witheither the continuous extraction or the intermittent extractiondescribed above. Thus the reaction may be conducted as a continuousreaction. In an example of a fully continuous system therefore, a twophase mixture comprises a reaction mixture phase, comprising theNHC-metal complex and an ionic liquid solvent, and an extraction liquidphase (e.g. THF) which is immiscible with the reaction mixture phase.The saccharide (optionally in a solvent) is then fed continuously intothe reaction mixture phase, where it reacts with the NHC-metal complexto form HMF, which is continuously extracted into the extractionsolvent. The extraction solvent is continuously removed and replaced atthe same rate with a fresh extraction solvent. The removed extractionsolvent is evaporated to generate the fresh extraction solvent, whichis, as mentioned above, fed continuously to the two phase mixture withany top-up extraction solvent that is required. The evaporation alsocontinuously generates HMF product which is then removed and stored orused as required.

An apparatus for conducting the process of the invention batchwise maycomprise a reactor vessel and a separator. The reactor vessel is adaptedto contain the reaction mixture and the extraction liquid. It maycomprise an agitator, for example a stirrer, a shaker, a sonicator orsimilar, or may not comprise an agitator. A take-off line leads from thereactor vessel to the separator and is positioned so as to be capable,in operation, of removing extraction liquid from the reactor vesselwithout removing reaction mixture therefrom. In the event that theextraction liquid has lower specific gravity than the reaction mixture,the take-off line may be located above the interface between theextraction liquid and the reaction mixture. The separator may be anydevice capable of separating the extraction liquid from the HMF product.It may for example be an evaporator or distillation apparatus. Theseparator has a return line for returning the extraction liquid to thereactor vessel after separation of the HMF. The return line may bedisposed so as to return the extraction liquid into the reactionmixture, so that the extraction liquid passes through the reactionmixture as it separates therefrom, thereby extracting HMF from thereaction mixture. Alternatively, the return line may be disposed so thatthe extraction liquid is not returned into the reaction mixture. It mayfor example be returned into extraction liquid that remains in thereactor vessel. In that event, HMF is extracted into the extractionliquid through the normal interface between the extraction liquid andthe reaction liquid. The take-off line, the separator or the return linemay be fitted with a pump (or more than one pump) so as to promote flowof the extraction liquid to and from the separator. They may be fittedwith one or more valves in order to ensure flow in the desired directionand prevent backflow. In some embodiments no pumps or valves arepresent. In such embodiments, correct liquid flow may be promoted bysituating the evaporator so that gravity causes the desired liquid flowsto occur. The separator may also be fitted with an HMF line for removingHMF from the separator. The HMF line may be maintained at a temperatureabove the melting point of HMF (about 30-34° C.). It may be fitted witha warmer to maintain the HMF line above the melting point of HMF.

The batchwise apparatus described above may be adapted to form acontinuous apparatus by providing a saccharide feed vessel coupled tothe reactor vessel by a feed line. The feed line may be disposed so thatthe saccharide is fed directly into the reaction mixture in the reactorvessel in use. In the event that the extraction liquid has lowerspecific gravity than the reaction mixture, the feed line may feed intothe reactor vessel below the interface between the extraction liquid andthe reaction mixture. The feed line and/or the feed vessel may be fittedwith a pump and/or a valve in order to promote desired flow ofsaccharide into the reactor vessel. In some instances one or other ofthese may not be required, for example a pump may not be required ifgravitational flow is enabled by suitable location of the feed vessel,and a valve may not be required if the pump performs both the functionof a valve and of a pump.

The metal complex of the N-heterocyclic carbene may be recycledfollowing removal of the hydroxymethylfurfural from the reactionmixture. This may comprise reusing a solution of the metal complex in asubsequent reaction. It may comprise isolating the metal complex fromthe reaction mixture, for example by solvent precipitation andfiltering/decanting, or by evaporation of the reaction mixture. Themetal complex so isolated may be used as is, or may be purified, e.g. bywashing with a suitable solvent, by reprecipitation or recrystallisationor by some other suitable method. In the event that a two phase processis used (as described above), the recycling may be achieved by addingfurther saccharide to the reaction mixture and contacting freshextraction liquid with the reaction mixture.

In the event that the reaction mixture comprises an ionic liquid, theionic liquid may be recycled following removal of thehydroxymethylfurfural from the reaction mixture. This may for examplecomprise distillation of the ionic liquid or it may comprise solventextraction of the ionic liquid, or it may comprise some other recyclingprocess. As described above for the metal complex, the ionic liquid neednot be separated in order to recycle it. Thus the reaction mixture,comprising the ionic liquid and the metal complex, may be simply reusedby addition of further saccharide. As also described earlier, this maybe converted to a continuous system by continuously feeding saccharideto the reaction mixture and continuously removing the HMF product fromthe reaction mixture by continuous extraction with an extraction liquid.

The HMF produced by the process described herein may be converted into afuel. Thus using the process of the invention as described herein, afuel, in particular a biofuel, may be made by converting a saccharide toHMF, and then the HMF may be used to make the fuel by known methods.

A particular embodiment of the invention provides a noveltetrahydrofuran (THF)-butyl-methyl imidazolium chloride (BMIMCl)biphasic system with tungsten salt catalyst for fructose conversion toHMF under mild reaction conditions. The novel tungsten salt catalystenables HMF to be efficiently synthesized at ≦50° C. in the ionic liquidsystem. The biphasic system has been successfully applied to acontinuous batch reaction process, and may be suitable for large-scalesynthesis of HMF from fructose. This is the first organic solvent-ionicliquid biphasic system that enables the conversion of sugars to HMF atlow temperatures (≦50° C.) using a novel tungsten salt catalyst.Compared to other systems, this approach is attractive for its mildreaction conditions. The new system may be applied in making biofuel andin the fine chemical industries.

The inventors have also developed a new protocol so that an organicsolvent-ionic liquid biphasic system could be used for productseparation in establishing a scalable continuous process. Afterscreening different metal salts, it was found that tungsten salts werethe most promising in catalyzing fructose conversion to HMF at lowtemperatures.

An ionic liquid-tungsten salt catalyst system has been developed thatcan effectively convert fructose to HMF at a much lower temperature(≦50° C.) than previously used. Disclosed herein is an ionicliquid-tetrahydrofuran (THF) biphasic system using the tungsten saltcatalyst or similar. This system offers a feasible large-scalecontinuous HMF production protocol under moderate temperatures andambient pressure. It represents the first efficient catalytic systemthat converts sugars to HMF at a reaction temperature of <8⁰° C. This isa notable achievement and advantageous system for many reasons. Firstly,the lower reaction temperature produces less by-products that causesystem contamination. Secondly, it allows lower boiling point solventsto be used as the mobile phase in the biphasic system, facilitating HMFproduct recovery by solvent distillation. Thirdly, the mild conditionslower the energy consumption and give rise to a longer system lifetime,which are important towards developing a sustainable biofuel system.

In a typical reaction protocol, 100 mg fructose was mixed with 500 mgbutyl-methyl imidazolium chloride (BMIMCl) and 5 mol % of WCl₆ catalyst.The reaction mixture was kept at 50° C. for 3-6 h. HMF was extracted byether (three times) with 58% yield. The HMF yield was confirmed bynuclear magnetic resonance (NMR) spectrum of the extracted product withan added external standard, and the results were confirmed by repeatedexperiments.

When N-heterocyclic carbene,1,3-bis(2,6-diisopropylphenyl)imidazolylidene (Ipr), was used as theligand, a slight higher HMF yield (65%) was achieved with the resultingIpr-WCl₆ catalyst. The Ipr/WCl₆ ratio and the type of base used in thesynthesis of Ipr-WCl₆ catalyst did not substantially affect the HMFyield: the HMF yields using Ipr-WCl₆, (Ipr)₂-WCl₆ and Ipr*-WCl₆ (Iprcarbene generated by NaH) catalysts were similar. When solid acidzeolite H—Y (CBV720) was used as a co-catalyst, a slightly higher HMFyield (69%) was obtained. Remarkably, the tungsten salt catalystfunctioned well at temperatures below 50° C. At 30° C., although theBMIMCl and fructose mixture behaved as a paste and was difficult tostir, a HMF yield of 53% was achieved after 4 h of reaction time. Thetemperature effect was inhibitory above 5⁰° C. Tungsten(IV) salts couldalso catalyze this reaction at 50° C. with slightly lower activities, ascompared to tungsten(VI) salts (see Table 2). Other salts such astitanium chloride, zirconium chloride and ruthenium chloride could alsocatalyze fructose conversion to HMF with yields of 43%, 47% and 42%,respectively (entries 12-14, Table 1).

TABLE 2 Conversion of fructose to HMF by metal catalysts in BMIMCl.^(a)Entry Catalyst Yield from fructose [%]^([b]) 1 WCl₆ 58 2 Ipr-WCl₆ 65 3Ipr*-WCl₆ ^([c]) 63 4 (Ipr)₂-WCl₆ 65 5 Ipr-WCl₆/H—Y zeolite 69 6 WCl₄ 617 Ipr-WCl₄ 62 8 (Ipr)₂-WCl₄ 65 9 Ipr-WCl₄/H—Y zeolite 59 10 CrCl₃ 3 11CrCl₂ 2 12 TiCl₄ 43 13 ZrCl₂ 47 14 RuCl₃ 42 ^(a)Reaction conditions: 500mg of BMIMCl, 100 mg of fructose, 5 mol % of catalyst, 50° C., 6 h.^([b])Yield was determined by the NMR spectrum of the extracted productwith an external standard. ^([c])Catalyst prepared using NaH.

The optimized Ipr-WCl₆ catalyst loading for this reaction at 50° C. was5 mol %. Lower catalyst loading would require a longer reaction time toachieve a high conversion, while higher catalyst loading only marginallyincreased the conversion.

Kinetic studies of this reaction using Ipr-WCl₆ showed that HMF yieldquickly reached 55% in 3 h, and slowly increased to the maximum yield65% in 6 h (see FIG. 6). On the other hand, the fructose amountremaining in the mixture sharply dropped to 12% in 90 min, and thenslowly decreased to about 2% in 6 h (see FIG. 1 (red curve)). The dashedcurve in FIG. 6 represents the sum of fructose and HMF masses in thereaction mixture. It demonstrated a clear minimum 40 mg at 90 min, andthen increased to 65 mg at 180 min. This suggested that fructose quicklyformed an intermediate(s), and subsequently formed HMF and by-products.The intermediate(s) existed in significant quantities in the reactionmixture early in the reaction.

The reaction can be described as follows, with fructoseconcentration=[F], intermediate concentration=[Int], HMFconcentration=[HMF], and by-product concentration=[BP].

It appears that the reaction rate is controlled by Equation (2) (k₁>k2).The existence of a large amount of intermediate will result in moreby-product ([BP]∝ k₃.[Int]^(n)>1). It is assumed that lower [Int], [HMF]and [H₂O] in the reaction mixture will lead to a higher HMF yield. Thiscan be achieved by using a biphasic continuous reaction system. In abiphasic continuous system, fructose can be continuously added in smallportion so that the intermediate concentration can be controlled. HMF(and water) can be extracted out of the ionic liquid and into THF insitu to push the reaction forward in Equation (2).

The ionic liquid-tungsten salt catalyst system allowed for theextraction of HMF from the ionic liquid phase at lower temperatures.This provided more options in selecting suitable organic solvents forthe biphasic system. The ideal solvent must form a separate phase fromthe ionic liquid, and have a boiling point above 50° C. The solventshould also be easily separated from the extracted HMF throughevaporation. Of the solvents that were screened, THF showed the greatestpotential. By using a batch biphasic reactor (FIG. 7(A)), 72% HMF yieldwas attained with the THF/BMIMCl system, which was higher than thatobtained with the monophase ionic liquid system. Furthermore, THF wasable to remove trace water produced during the dehydration of fructose,keeping the reaction clean. Toluene suppressed the reaction under thesame conditions, giving only 25% HMF yield, whereas EtOAc led to 59% HMFyield. In FIG. 7A, ionic liquid (white) contains BMIMCl, Ipr-WCl₆ andfructose, while the organic phase (gray) contains THF. HMF is extractedinto the THF phase and separated through an evaporation step; THF can bereused upon evaporation-condensation. By contrast, in the continuousbatch process described below fructose is added continuously or batch bybatch.

After modifications to the batch reactor system, a continuous batchreaction process was tested (FIG. 7(B)). A constant amount of fructosewas added to the reactor system every 6 hours, and the THF phase wascollected and refreshed every 90 minutes. The reaction system was keptactive without interruption between different batch runs. Throughcollection of the THF phase, the HMF yield of every 6 hour batch wasquantified. Fructose concentration was also monitored at these 6 hourintervals. It was found that the HMF yield actually increased steadilyfrom 70% (first batch run) to 82% (third batch run) (see FIG. 8). Thismight be due to the accumulation of small amounts of unreacted fructoseor intermediates from the previous batch(es). In fact, the remainingfructose at the end of each batch run was very low (2-3 mg). The averageHMF yield at the end of each batch run stabilized at about 80%.Remarkably, the Ipr-WCl₆ catalyst-ionic liquid system retained a highcatalytic activity over multiple batch runs, may be the major reason forthe long system lifetime.

In conclusion, a novel THF-BMIMCl biphasic system with tungsten saltcatalyst for fructose conversion to HMF under mild reaction conditionshas been developed. With the tungsten salt catalyst, HMF was efficientlysynthesized at ≦50° C. in the ionic liquid. The biphasic system wassuccessfully applied to a continuous batch reaction process, and mightbe suitable for the large-scale synthesis of HMF from fructose.

EXAMPLES General Information

All solvents and chemicals were used as obtained from commercialsuppliers, unless otherwise indicated. Centrifugation was performed onEppendorf Centrifuge 5810R (4000 rpm, 10 min). ¹H and ¹³C NMR spectrawere recorded on Bruker AV-400 spectrometer (400 MHz). Fructose wasquantified using SU-300 Sugar Analyzer (TOA-DKK Corp.).

Preparation of Ipr-WCl₆ Catalysts

1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (467 mg, 1.1 mmol)was mixed with KO^(t)Bu (123 mg, 1.1 mmol) in 20 ml of anhydrousN,N-dimethylformamide (DMF). The reaction mixture was allowed to stirfor 1 h at room temperature before WCl₆ (397 mg, 1 mmol) was added tothe mixture, which was then heated to 80° C. and stirred for another 6h. The reaction mixture was cooled to room temperature and filtered. Thegreen DMF solution was directly used as the catalyst stock solution.Alternatively, the catalyst solution was dried. The resulting greenpowder was washed with ether and THF, and dried under vacuum.

Conversion of Sugars to HMF

Batch Reaction: In a typical reaction, 0.556 mmol of fructose (100 mg)was dissolved in BMIMCl (500 mg), and the tungsten salt catalyst (5 mol%) was added. The reaction mixture was then heated to 50° C. for 3-6 h.It was allowed to cool to room temperature before 1 ml of water wasadded. HMF was extracted 3 times with 15 ml of ether.

Biphasic Batch Reaction: In a typical reaction, 0.556 mmol of fructose(100 mg) was dissolved in BMIMCl (500 mg), and the tungsten saltcatalyst (5 mol %) and THF (10 ml) were added. The reaction mixture wasthen heated to 50° C. for 3-6 h. The THF phase was refreshed 3 timesduring the reaction, and all three THF portions were combined for HMFquantification.

Continuous Biphasic Batch Reaction: In a typical reaction, 0.556 mmol offructose (100 mg) was dissolved in BMIMCl (500 mg), and the tungstensalt catalyst (5 mol %) and THF (10 ml) were added. The reaction mixturewas then heated to 50° C. for 3-6 h. The THF phase was refreshed 3 timesduring the reaction, and all three THF portions were combined for HMFquantification. After 6 h, a new batch of 100 mg of fructose was addeddirectly to the reaction mixture to start the second batch run. The HMFyield and the fructose remaining were monitored at the end of each batchrun.

Quantification of HMF Yield

The combined ether (or THF) extracts were concentrated under vacuum atroom temperature. A known amount of the external standard, mesitylene,was added to the product container with deuterium solvent (e.g. DMSO-d₆,CDCl₃, CD₃OD and acetone-d₆). The HMF yield was obtained from ¹H NMRspectrum using mesitylene as the external standard. It was calculated bythe integration of proton peaks of HMF (6.589 ppm) and mesitylene (6.745ppm).

1. A process for making hydroxymethylfurfural comprising: (i) providinga reaction mixture comprising a saccharide and a metal complex of anN-heterocyclic carbene wherein said saccharide is a hexose or a mixtureof hexoses, or a dimer, oligomer or polymer or copolymer of a hexose ora mixture thereof; and (ii) allowing the saccharide to react in thereaction mixture to form hydroxymethylfurfural; wherein steps (i) and(ii) are conducted at about 70° C. or below.
 2. The process of claim 1wherein the saccharide comprises a monosaccharide.
 3. The process ofclaim 2 wherein the monosaccharide comprises fructose, glucose or amixture of these.
 4. The process of claim 1 wherein the reaction mixtureadditionally comprises an ionic liquid.
 5. The process of claim 4wherein during step (ii) the reaction mixture is continuously orintermittently contacted with a solvent for hydroxymethylfurfural, saidsolvent being immiscible with the ionic liquid, so as to extract thehydroxymethylfurfural into the solvent.
 6. The process of claim 4wherein the reaction mixture is contacted with a solvent forhydroxymethylfurfural after step (ii), said solvent being immisciblewith the ionic liquid, so as to extract the hydroxymethylfurfural intothe solvent.
 7. The process of claim 1 wherein the metal complex of theN-heterocyclic carbene is a metal complex of a monomeric N-heterocycliccarbene.
 8. The process of claim 7 wherein the metal complex of theN-heterocyclic carbene is a metal complex of an imidazol-2-ylidene or ofan imidazolin-2-ylidine.
 9. The process of claim 1 wherein the metalcomplex is selected from the group consisting of a tungsten complex, atitanium complex, a zirconium complex, a ruthenium complex and a mixtureof any two or more of these types of complex.
 10. The process of claim 9wherein the metal complex is a tungsten complex of an imidazol-2-ylideneor of an imidazolin-2-ylidine.
 11. The process of claim 1 comprising thestep of generating the metal complex of the N-heterocyclic carbene. 12.The process of claim 11 wherein the step of generating the metal complexof the N-heterocyclic carbene comprises reacting a nitrogen heterocyclesalt with a base in the presence of a salt of the metal.
 13. The processof claim 12 wherein the base is potassium t-butoxide.
 14. The process ofclaim 11 comprising removing a solvent in which said step of generatingis conducted, said removing being conducted after said generating. 15.The process of claim 1, said process being a continuous reaction. 16.The process of claim 1 wherein the metal complex of the N-heterocycliccarbene is recycled following removal of the hydroxymethylfurfural fromthe reaction mixture.
 17. The process of claim 4 wherein the ionicliquid is reused following removal of the hydroxymethylfurfural from thereaction mixture.
 18. A process for making a fuel comprising: (i)providing a reaction mixture comprising a saccharide and a metal complexof an N-heterocyclic carbene wherein said saccharide is a hexose or amixture of hexoses, or a dimer, oligomer or polymer or copolymer of ahexose or a mixture thereof; (ii) allowing the saccharide to react inthe reaction mixture to form hydroxymethylfurfural; and (iii) convertingthe hydroxymethylfurfural to the fuel; wherein steps (i) and (ii) areconducted at about 70° C. or below.
 19. The process of claim 18comprising the step of separating the hydroxymethylfurfural from thereaction mixture prior to step (iii).
 20. The process of claims 18wherein the metal complex of the N-heterocyclic carbene is a tungstencomplex of an imidazol-2-ylidene or of an imidazolin-2-ylidine.